Non-mucoadhesive film dosage forms

ABSTRACT

Orally disintegrating film dosage forms for delivering active pharmaceutical agents, methods of formulating the dosage forms to retard absorption through the oral mucosa, and methods of using the dosage forms for the treatment of various medical conditions are provided.

RELATIONSHIP TO PRIOR APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/443,414, filed Mar. 27, 2009, which is a U.S. National Stageapplication of, and claims the benefit pursuant to 35 U.S.C. §371 of,International Patent Application Serial No. PCT/EP2007/008579, filedOct. 2, 2007, which claims the benefit, pursuant to 35 U.S.C. §119(e),of U.S. Provisional Patent Application No. 60/848,965, filed Oct. 2,2006 (now abandoned). The entire contents of each of these applicationsis hereby incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to orally disintegrating film dosage formsfor delivering active pharmaceutical agents, methods of formulating thedosage forms to promote gastrointestinal absorption comparable toimmediate release solid oral dosage forms, and to methods of using thedosage forms for the treatment of various medical conditions.

BACKGROUND OF THE INVENTION

Orally administered film strip dosage forms have been recently developedfor the pharmaceutical industry, and are currently used for the sale ofseveral popular over-the-counter drug products, including Listerine®breath strips, Triaminic® thin strips (active agent=diphenhydramineHCl), and Sudafed PE™ quick dissolve strips (activeingredient=phenylephrine HCl). The absolute bioavailability ofdiphenhydramine when ingested orally is approximately 61%, and the timeto maximum serum concentration is about 3-4 hours. Phenylephrine issubject to extensive presystemic metabolism in the gut wall, such thatthe absolute bioavailability of phenylephrine when ingested orally isapproximately 40% relative to intravenous dosing, and peak plasmaconcentrations are achieved in about 1-2 hours.

In addition, several manufacturers have proposed formulations that couldbe used to deliver prescription drugs. The vast majority of theseformulations are “mucoadhesive” formulations designed for adhesion ofthe dosage form to mucosal tissue in the mouth, and transmission of thedrug from the dosage form through the mucosal tissue into the systemiccirculation. As described in U.S. Pat. No. 6,750,921 to Kim et al.,film-forming agents have been used to manufacture drug deliveryformulations for percutaneous or transdermal application, but thesenecessarily involve an adhesive composition to retain the agent in situlong enough to cause sustained release of the active ingredient.Bioerodible films are described in Tapolsky et al., U.S. Pat. No.5,800,832. The films have an adhesive layer and a non-adhesive backinglayer and are intended to adhere to the mucosal surface. Biegajski etal., U.S. Pat. No. 5,700,478, describes a water-solublepressure-sensitive mucoadhesive suitable for use in a mucosal-lined bodycavity.

The purported advantage of these mucoadhesive films resides in theirability to bypass the gastrointestinal tract, and barriers in thegastrointestinal tract to drug absorption such as first pass metabolismand decomposition of the active ingredient in the stomach. An additionaladvantage for these dosage forms, when compared to tablets, capsules andother dosage forms that must be swallowed, is that some patientpopulations have difficulty swallowing, such as children and theelderly.

Until now the prior art has been focused principally on improving thedelivery profile of a given pharmaceutical agent with this dosage form,by increasing its rate of dissolution or absorption, or bypassingmetabolic processes that reduce the bioavailability of the drug. Theprior art has not appreciated that an innovator's drug product, be it atablet, capsule, or other oral dosage form, has already proven itselfeffective through rigorous clinical testing, and that the innovator'sproduct may already provide the optimum bioavailability ofpharmaceutical agent. What is needed is a film product that mimics thepharmacokinetics of an innovator's product, and that follows the samemetabolic and bioabsorption pathways as the innovator's product, toensure that the dosage form achieves the proven clinical efficacy of theinnovator product.

OBJECTS OF THE INVENTION

Accordingly, it is an object of the present invention to providenon-mucoadhesive orally disintegrating film dosage forms that mimic thepharmacokinetic profile of orally administered drug products such astablets, capsules, liquid suspensions, and orally dissolving/dispersingtablet (ODT).

Another object of the invention is to provide non-mucoadhesive orallydisintegrating film dosage forms that follow the same metabolic andbioabsorption pathways through the gastrointestinal tract as existingorally administered drugs, such as tablets, capsules, liquidsuspensions, and orally dissolving/dispersing tablet (ODT).

Still another object of the present invention is to provide methods offormulating and testing non-mucoadhesive orally disintegrating filmdosage forms so that they follow the same metabolic and bioabsorptionpathways, and obtain the same pharmacokinetic profiles, as existingorally administered drugs such as tablets, capsules, liquid suspensions,and orally dissolving/dispersing tablet (ODT).

Another object of the present invention is to provide methods oftreatment using the film dosage forms of the present invention, andmethods that promote bioequivalence to orally administered drug productssuch as tablets, capsules, liquid suspensions, and orallydissolving/dispersing tablet (ODT).

Yet another object of the present invention is to provide techniques andmethodologies for retarding the absorption of drugs from orallydisintegrating films through the oral mucosa.

SUMMARY OF THE INVENTION

The present invention provides film dosage forms that are formulated oradministered for gastrointestinal absorption of the activepharmaceutical agent, and that are bioequivalent to and interchangeablewith existing orally administered drug products. These film dosage formsare non-mucoadhesive; they quickly disintegrate in the mouth whenexposed to saliva; and they are absorbed predominantly through thegastrointestinal tract. Most importantly, these dosage forms arespecially formulated to meet exacting bioavailability requirements, orto be bioequivalent to existing orally administered dosage forms.

Therefore, in a first principal embodiment, the invention provides anon-mucoadhesive orally disintegrating film, able to disintegrate uponcontact with saliva in the buccal cavity within about sixty seconds,comprising a defined amount of an active pharmaceutical agent, ahydrophilic binder and a water-soluble diluent, wherein: (a) said filmis formulated for delivery of said active agent through thegastrointestinal tract when applied to the tongue; (b) said filmcomprises from about 0.05% to about 50% (w/w) of said activepharmaceutical agent, based on the total weight of the formulation; and(c) said film is bioequivalent to an immediate release tablet or ororally dissolving/dispersing tablet (ODT) that comprises said activepharmaceutical agent in said defined amount.

In one embodiment, the immediate release tablet or orallydissolving/dispersing tablet (ODT) is characterized by slow or delayedbioavailability (i.e. a “slowly bioavailable drug”). The inventors havedeveloped orally disintegrating film dosage forms which, it is believed,will unexpectedly be bioequivalent to these conventional “slowlybioavailable drugs,” without any substantial modification of the releasecharacteristics from the film dosage form, as long as the film candisintegrate when placed on the tongue within about sixty seconds. Thus,for example, the immediate release dosage form can be characterized by:

-   -   a T_(max) (i.e. time to maximum plasma concentration) of greater        than about 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5        hours, 4.0 hours, 4.5 hours or even 5.0 hours;    -   a disintegration time of greater than about 10 or 20 minutes,        but less than about 90 or 60 minutes;    -   a 90% dissolution time of greater than about 10 or 20 minutes,        but less than about 90 or 60 minutes; and/or    -   a film coating that delays the release and absorption of active        ingredient from the dosage form.

Of course, the invention could also be practiced with drugs having otherpharmacokinetic profiles, and in other embodiments the T_(max) of thedrug is less than 3.0, 2.5, 2.0, 1.5 or 1.0 hours.

In another embodiment, the film strip of the present invention, or theimmediate release dosage form, can be defined by its pharmacokinetics,and in one embodiment, the film strip or immediate release dosage formhas an absolute bioavailability of greater than 65%, 75%, 85% or even95% when administered orally. In another embodiment, the film strip orimmediate release dosage form has an absolute bioavailability that isgreater than about 45%, 50%, or 55%, and peak plasma concentrations(C_(max)) in less than 3.0, 2.5 or 2.0 hours. Finally, because the filmdosage form is specially formulated or administered for gastrointestinalabsorption, the film dosage form has a comparable absolutebioavailability or T_(max) as an immediate release tablet or capsule ororally dissolving/dispersing tablet (ODT) that comprises the same amountof active pharmaceutical agent.

The films themselves, and the methods of using the films, arecharacterized by a number of features that ensure their bioequivalenceto a comparable immediate release tablet or capsule or orallydissolving/dispersing tablet (ODT), including:

-   -   the films may be engineered or used so that the active        pharmaceutical agent is swallowed and absorbed predominantly or        entirely through the gastrointestinal tract, instead of being        absorbed through the oral mucosa;    -   if necessary, the films or active pharmaceutical agents may be        formulated so that absorption of active pharmaceutical agent        through the oral mucosa is retarded;    -   the films are typically designed for rapid disintegration when        taken orally, and are most often swallowed in less than thirty        or sixty seconds after administration;    -   the films are usually applied directly onto the tongue to        promote mixing with the saliva and subsequent swallowing of the        active ingredient, and thereby discourage mucosal absorption;        and    -   water could be additionally swallowed within about thirty or        sixty seconds after administration of the film, to further        promote swallowing of the active agent and gastrointestinal        absorption.

A particularly preferred drug of the present invention is a donepezilfilm strip, which demonstrates bioequivalence to existing immediaterelease tablets of donepezil hydrochloride, and which exhibits a peakplasma concentration of donepezil in from about three to about fourhours. Another preferred drug is an ondansetron film strip, which ischaracterized by an absolute bioavailability of ondansetron of fromabout 45% to about 75%, and which is formulated as a base to retardabsorption through the oral mucosa. Other preferred drugs are set forthin the detailed description of invention and examples which follow.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION OF THE FIGURES

FIG. 1 is a comparison of dissolution profiles over time comparing threecommercially available formulations of ondansetron with two ondansetronRapidFilm formulations, as described in Table 4. The upper line at 1minute is Zofran® 4 mg Zydis® Lingual; the second line at 1 minute isZofran® 8 mg Zydis® Lingual; the third line is ondansetron 8 mgRapidFilm; the fourth line is ondansetron 4 mg RapidFilm; the bottomline is Zofran® 8 mg Filmtablet.

FIG. 2 depicts mean (FIG. 2A) and log mean (FIG. 2B) drug plasmaconcentration profiles versus time for 8 mg ondansetron RapidFilminvestigational product versus Zofran® 8 mg Lingual orallydisintegrating tablets, as described in Table 6.

FIG. 3 is a comparison of dissolution profiles over time comparingcommercially available donepezil hydrochloride immediate releasetablets, commercially available donepezil hydrochloride orallydisintegrating tablets, and four donepezil hydrochloride RapidFilmformulations, as described in Tables 9-14. The top line at 3 minutes isRapidFilm prototype F; the second line at 3 minutes is Aricept® filmtablets; the third line at 3 minutes is RapidFilm prototype E; thefourth line at 3 minutes is RapidFilm prototype A; the fifth line at 3minutes is Aricept® ODT; the bottom line at 3 minutes is RapidFilmprototype C.

FIG. 4 is a stacking x-ray diffraction pattern for three samples—(1)ondansetron base Form B polymorph, (2) RapidFilm comprising 4 mg ofondansetron having the formulation of Table 4 and stored at 40° C., and(3) RapidFilm comprising 4 mg of ondansetron having the formulation ofTable 4 (OND 013 OD), and stored at 60° C. (84201506).

FIG. 5 is a DSC heating curve for donepezil HCl Form I.

FIG. 6 is an X-ray diffraction pattern for donepezil HCl Form I.

FIG. 7 is an X-ray diffraction pattern for ondansetron base Form B.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of preferred embodiments of the inventionand the Examples included therein.

DEFINITIONS AND USE OF TERMS

As used in this specification and in the claims which follow, thesingular forms “a,” “an” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “aningredient” includes mixtures of ingredients, reference to “an activepharmaceutical agent” includes more than one active pharmaceuticalagent, and the like.

The term “disintegrate” has its usual and customary meaning in thepharmaceutical arts, as described in <701> of the U.S. Pharmacopoeia(2005 USP/NF) for uncoated tablets, using a basket rack assemblyoperating at 30 cycles per minute through a distance of 5.5 cm, in adisintegration medium at 37° C. When disintegration requirements arediscussed herein, they are preferably met under the foregoing testingconditions, at a pH of 4.0 or 6.8. A film or other dosage form is saidto be “disintegrated” if it is completely disintegrated, a state inwhich any residue of the unit remaining on the screen of the testapparatus, or in the mouth, is a soft mass having no palpably film core,or fragments of a tablet coating or capsule shell. Disintegration thusdoes not imply complete dissolution of the dosage unit or even theactive constituent, although a dissolved dosage unit would typically becompletely disintegrated. When reference to Ph. Eur. 2.9.1(disintegration) is made herein, it will be understood that thedisintegration conditions described above under <701> USP can also beemployed.

The term “dissolution” also has its usual and customary meaning in thepharmaceutical arts, as described in <711> and <724> of the U.S.Pharmacopoeia (2005 USP/NF). Therefore, a film is said to be “dissolved”if, upon testing by the method of U.S. Pharmacopoeia (2005 USP/NF), theamount of active agent dissolved in the dissolution medium exceeds apredetermined percentage. When dissolution conditions are given, it willbe understood that stirring preferably occurs in 0.1N hydrochloric acidbuffer (pH=2), or at pH 1.2, pH 4.0 or 6.8, at 37° C., using the paddlemethod at 50 rpm in a type II dissolution apparatus.

The term “immediate release,” when used in this document, refers to adosage form that allows the drug to dissolve in the gastrointestinalcontents, with no intention of delaying or prolonging the dissolution orabsorption of the drug. The term includes tablets, capsules, liquidsuspensions, orally disintegrating/dispersing tablet (ODT), and otherdosage forms intended for immediate release of active ingredient uponadministration (preferably oral administration). In contrast, a“modified release” dosage form is a dosage form whose drug releasecharacteristics of time course and/or location are chosen to accomplishtherapeutic or convenience objectives not offered by conventional dosageforms such as a solution or immediate release dosage form. Modifiedrelease solid oral dosage forms include both delayed and extendedrelease drug products.

An “immediate release” dosage form as used herein preferably refers to adosage form adapted to release at least 80% or 90% of an activepharmaceutical ingredient in 60 minutes or less when measured in a typeII dissolution apparatus (as described in <711> and <724> of the U.S.Pharmacopoeia (2005 USP/NF)), in 0.1N hydrochloric acid buffer (pH=2),or at pH 1.2, pH 4.0 or 6.8, at 37° C. In a preferred embodiment, atleast 80%, 90% or 100% is dissolved in no more than 45 or 30 minutes.Stirring preferably occurs using the paddle method at 50 rpm. Finally,it will be understood that when reference to Ph. Eur. 2.9.3 (paddle overdisc) is made herein, the foregoing dissolution conditions under <711>and <724> of the U.S. Pharmacopoeia (2005 USP/NF) can be applied.

An immediate release solid oral dosage form is considered “rapidlydissolving” when not less than 80% of the label amount of the drugsubstance dissolves (i.e. releases) within 15 minutes in each of thefollowing media: (1) pH 1.2, (2) pH 4.0, and (3) pH 6.8, in accordancewith Q6 ICH-guideline.

A “orally dissolving or orally dispersible tablet” (“ODT”) refers to anuncoated tablet intended to be placed in the mouth where it can disperserapidly before being swallowed, as described in Eur. Ph. 5.0. An ODTdisintegrates within three minutes when tested according to thedisintegration testing described herein.

The term “non-mucoadhesive” means that the dosage form is not designedfor administration of the active pharmaceutical agent through the oralmucosa. I.e. the dosage form is not designed to adhere to the mucosalsurfaces of the buccal cavity as an intact film or disintegrated filmresidue.

Unless specified otherwise, the term “wt. %” as used herein withreference to the final product (i.e., the film, as opposed to theformulation used to create it), denotes the percentage of the total dryweight contributed by the subject ingredient. This theoretical value candiffer from the experimental value, because in practice, the filmtypically retains some of the water and/or ethanol used in preparation.

When doses are given for a drug and its salt, it will be understood thatthe calculated dose is based on the molecular weight of the activepharmaceutical ingredient, which includes the cationic and anionicspecies in the case of a salt, and just the base when the activeprinciple is not present as a salt. In addition, when reference is madeto the salt of a drug and pharmaceutically acceptable salts thereof, itwill be understood that salts of the base form of the base drug areintended.

When ranges are given by specifying the lower end of a range separatelyfrom the upper end of the range, it will be understood that the rangecan be defined by selectively combining any one of the lower endvariables with any one of the upper end variables that is mathematicallypossible.

When used herein the term “about” or “ca.” will compensate forvariability allowed for in the pharmaceutical industry and inherent inpharmaceutical products, such as differences in product strength due tomanufacturing variation and time-induced product degradation. The termallows for any variation which in the practice of pharmaceuticals wouldallow the product being evaluated to be considered bioequivalent to therecited strength of a claimed product.

The term “absolute bioavailability” refers to the availability of theactive drug in systemic circulation after non-intravenous administration(i.e., after oral, rectal, transdermal, subcutaneous administration). Inorder to determine absolute bioavailability of a drug, a pharmacokineticstudy must be done to obtain a plasma drug concentration versus timeplot for the drug after both intravenous (IV) and non-intravenousadministration. The absolute bioavailability is the dose-corrected areaunder curve (AUC) non-intravenous divided by AUC intravenous.

When pharmacokinetic parameters are given herein (i.e. T_(max), absolutebioavailability, etc.), it will be understood that they can refer to themean, median, or individual observed pharmacokinetics, and that meanpharmacokinetics are intended when claimed unless stated to thecontrary.

Discussion

As discussed above, the invention provides a physiologically acceptablefilm that is particularly well adapted to disintegrate rapidly whenplaced on the tongue of a patient, and to facilitate gastrointestinalabsorption of the pharmaceutically active agent. The film and activeagent need not dissolve entirely in the mouth, and preferably the filmis not entirely dissolved. When tested according to Ph. Eur. 2.9.3,paddle over disc, the film preferably dissolves (at least 80% or 100%active agent release) within about 15, 10 or 5 minutes, when tested atpH 1.2, 4.0 or 6.8.

The film may also be characterized by the time it takes to disintegratecompletely, and it preferably disintegrates to a soft residue withinabout 10, 20, 30 or 60 seconds of administration, after which it isswallowed. These disintegration times are preferably observed in theoral cavity when the film is administered, as well as when tested fordisintegration using the method described in Ph. Eur. 2.9.1. The promptdisintegration and swallowing of the film helps to assuregastrointestinal absorption of the dosage form. The film is not of theconventional mucoadhesive type, designed to deliver active agenttransmucosally.

In one embodiment, the film is defined by its long T_(max), and invarious embodiments, the film has a T_(max) of greater than about 3.0,3.5, 4.0, 4.5, or 5.0 hours. Alternatively or in addition, the film canbe defined by the absolute bioavailability (i.e. total extent ofabsorption) of the active ingredient and, in various embodiments, thefilm has an absolute bioavailability that is greater than about 45%,55%, 65%, 75%, 85% or even 95%. In still another embodiment, the film isdefined by the rate or extent of absorption of active agent into thebloodstream, in addition or alternatively to the absolutebioavailability of the active agent. For example, the film can bedefined by T_(max) (i.e. time to maximum concentration of the activeagent in plasma) and, in various embodiments, the film has a T_(max)less than about 3.0, 2.5, 2.0 or even 1.5 or 1.0 hours. Alternatively orin addition, the film can be defined by an absolute bioavailabilitygreater than about 45%, 50%, or 55%.

Therefore, in another embodiment the invention provides anon-mucoadhesive orally disintegrating film, able to disintegrate uponcontact with saliva in the buccal cavity within about sixty seconds,comprising a defined amount of an active pharmaceutical agent, or apharmaceutically acceptable salt thereof, a hydrophilic binder and awater-soluble diluent, wherein: (a) said film is formulated for deliveryof said active agent through the gastrointestinal tract when applied tothe tongue; (b) said film comprises from about 0.05% to about 50% (w/w)of said active pharmaceutical agent, based on the total weight of theformulation; and (c) said film is characterized by one or more of thefollowing pharmacokinetic parameters: (i) a T_(max) of greater thanabout 4.5 hours; (ii) an absolute bioavailability of greater than 65%,and optionally a T_(max) greater than about 1.5 hours; or (iii) aT_(max) of less than about 3.0 hours, and an absolute bioavailabilitygreater than about 45%.

In another embodiment, the invention is defined by its bioequivalence toan immediate release dosage tablet or capsule or orallydissolving/dispersing tablet (ODT) that contains the same amount ofactive pharmaceutical agent. In particular, the invention provides anon-mucoadhesive orally disintegrating film, able to disintegrate uponcontact with saliva in the buccal cavity within about sixty seconds,comprising a defined amount of an active pharmaceutical agent, or apharmaceutically acceptable salt thereof, a hydrophilic binder and awater-soluble diluent, wherein: (a) said film is formulated for deliveryof said active agent through the gastrointestinal tract when applied tothe tongue; (b) said film comprises from about 0.05% to about 50% (w/w)of said active pharmaceutical agent, based on the total weight of theformulation; and (c) said film is bioequivalent to an immediate releasetablet or capsule or orally dissolving/dispersing tablet (ODT) thatcomprises said active pharmaceutical agent or a pharmaceuticallyacceptable salt thereof in said defined amount (i.e. a “referenceproduct”).

The reference product can be defined by various pharmacokinetic orphysical properties. For example, the reference product could becharacterized by its absolute bioavailability, and preferably theabsolute bioavailability is greater than about 65%, 75%, 85% or even 95%when administered orally, and/or a T_(max) greater than about or 4.5hours. The reference product could also be characterized by its T_(max)and/or absolute bioavailability, i.e. a T_(max) less than about 3.0,2.5, 2.0 or even 1.5 or 1.0 hours, and/or an absolute bioavailabilitygreater than about 45%, 50%, or 55%.

Alternatively, the reference product could be characterized by itsdisintegration time which, in various embodiments could exceed 5, 10,20, 30, 40 or 45 minutes, when tested according to Ph. Eur. 2.9.1, andpreferably would be less than 60, 75 or 90 minutes. The referenceproduct could also be defined by its dissolution time. Dissolution timesfor the comparative reference products of the present invention, whentested according to Ph. Eur. 2.9.3, based on the time it takes todissolve 75, 80, 85, 90 or 95 wt. % of the drug substance, when testedat pH 1.2, 4.0 and/or 6.8, are preferably greater than about 5, 10, 20,30, 40 or 45 minutes, and less than about 90, 75 or 60 minutes. In apreferred embodiment, the dissolution profile for the reference productis in accordance with the following specification: not less than 70, 80,90 or 95% dissolved after 60 minutes when tested according to Ph. Eur.2.9.3 (paddle over disc). In one embodiment, the reference product is acapsule, optionally characterized by a gelatin shell. In anotherembodiment, the reference product is a tablet, optionally characterizedby a film or enteric coating. In another embodiment, the referenceproduct is a orally dissolving/dispersing tablet (ODT).

The film can also be characterized by various physical characteristics,including its structure, size and shape. For example, in one embodiment,the film is a single layer homogeneous film. In another embodiment, thefilm has a weight of from about 30 to about 150 milligrams, preferablyfrom about 40 to about 120 milligrams. The film may vary in thicknessanywhere from about 10 to about 200 microns, and preferably does notexceed 8 or 7 cm² in surface area.

The invention also provides various methods of treatment, based on theparticular active agent involved, that rely on one or more of severaldefining characteristics, including the placement of the dosage form onthe tongue, swallowing the dosage form within ten, twenty, thirty,forty-five or sixty seconds, and swallowing the dosage form with orwithout water. In yet another embodiment, therefore, the inventionprovides a method of treatment comprising: (a) providing anon-mucoadhesive orally disintegrating film, able to disintegrate uponcontact with saliva in the buccal cavity within about sixty seconds,comprising a defined amount of an active pharmaceutical agent, or apharmaceutically acceptable salt thereof, a hydrophilic binder and awater-soluble diluent: (b) placing said film on the tongue to produce adisintegrated film residue; and (c) swallowing said residue within aboutsixty seconds of step (b), so that the pharmaceutical agent ispredominantly absorbed through the gastrointestinal tract; wherein: (i)said film is bioequivalent to an immediate release tablet or capsule ororally dissolving/dispersing tablet (ODT) that comprises said activepharmaceutical agent or a pharmaceutically acceptable salt thereof insaid defined amount; (ii) said film has a T_(max) greater than about 4.5hours; (iii) said film has an absolute bioavailability of greater thanabout 65%, and optionally a T_(max) greater than about 1.5 hours; or(iv) said film has an absolute bioavailability of greater than about45%, and a T_(max) of less than about 3.0 hours; (v) said film has aT_(max) less than about 1.5 hours.

Formulating for Bioequivalence

In still another embodiment, the invention provides methods offormulating the film dosage form, to ensure bioequivalence between thefilm and an immediate release dosage form containing the same amount ofthe same active pharmaceutical agent. In like manner, the inventionprovides film dosage forms that are formulated according to thesemethods, and methods of treatment that rely upon such dosage forms.

Thus, in another embodiment, the invention provides a method of making abioequivalent non-mucoadhesive orally disintegrating film, comprising:(a) providing an orally swallowed dosage form that comprises an activepharmaceutical agent in a defined amount, and that is characterized by(i) gastrointestinal absorption when swallowed, and (ii) a firstpharmacokinetic profile; (b) formulating a first batch ofnon-mucoadhesive orally disintegrating film, able to disintegrate uponcontact with saliva in the buccal cavity within about sixty seconds,that comprises said active agent in said defined amount, and that ischaracterized by (i) a defined formulation, (ii) gastrointestinalabsorption when dissolved orally, and (iii) a second pharmacokineticprofile that is bioequivalent to said first pharmacokinetic profile; and(c) clinically testing said orally administered dosage form and saidorally disintegrating film for bioequivalence.

In still another embodiment the method further includes (a) measuring afirst dissolution or disintegration profile for said orallydisintegrating film from said first batch; (b) preparing a second batchof non-mucoadhesive orally disintegrating film that is characterized bysaid defined formulation; (c) measuring a second dissolution ordisintegration profile for said orally disintegrating film from saidsecond batch; and (d) comparing said first and second dissolution ordisintegration profiles for equivalence or sameness (i.e. withinacceptable deviations for pharmaceutical products in the pharmaceuticalindustry).

Bio equivalence Testing

Bioequivalence testing typically requires an in vivo test in humans inwhich the concentration of the active ingredient or active moiety, and,when appropriate, its active metabolite(s), in whole blood, plasma,serum, or other appropriate biological fluid is measured as a functionof time. Defined as relative bioavailability (“BA”), bioequivalence(“BE”) involves a comparison between a test and reference drug product.Although BA and BE are closely related, BE comparisons normally rely on(1) a criterion, (2) a confidence interval for the criterion, and (3) apredetermined BE limit.

A standard in vivo BE study design is based on the administration ofeither single or multiple doses of the test and reference products tohealthy subjects on separate occasions, with random assignment to thetwo possible sequences of drug product administration. Statisticalanalysis for pharmacokinetic measures, such as area under the curve(AUC) and peak concentration (C_(max)), is preferably based on theso-called “two one-sided tests procedure” to determine whether theaverage values for the pharmacokinetic measures determined afteradministration of the test and reference products are comparable. Thisapproach is termed average bioequivalence and involves the calculationof a 90% confidence interval for the ratio of the averages (populationgeometric means) of the measures for the test and reference products. Toestablish BE, the calculated confidence interval should fall within a BElimit, i.e. 80-125% for the ratio of the product averages. Furtherdetail regarding BE procedures can be found in FDA's July 1992 GuidanceDocument entitled “Statistical Procedures for Bioequivalence StudiesUsing a Standard Two-Treatment Crossover Design,” the contents of whichare incorporated herein by reference.

Film Formulation

Preferred films according to the invention comprise a pharmaceuticallyactive agent, a film-forming agent, and at least one of the followingadditional ingredients: water, antimicrobial agents, water solublediluents such as plasticizing agents, softeners, and fillers, flavoringagents, saliva stimulating agents, cooling agents, stabilizers,surfactants, stabilizing agents, emulsifying agents, thickening agents,binding agents, coloring agents, sweeteners, fragrances, triglycerides,preservatives, polyethylene oxides, propylene glycol, and the like.

In a preferred embodiment, the film comprises one or more ingredientsthat act both as water soluble binding agents and hydrophilic polymers,such as polyvinyl alcohol, polyethylene glycol (“PEG”), propyleneglycol, polyethylene oxide, and starches, celluloses, gelatines and thelike. Therefore, when it is stated herein that a formulation comprises awater soluble binding agent and a hydrophilic polymer, it will beunderstood that these two agents may be describing one solitaryingredient. The finished film product preferably comprises from about 40to about 80 wt. % of these ingredients, and more preferably from about50 to about 75 wt. %. The active agent preferably makes up from 5 to 20wt. % of the finished film formulation, more preferably from about 8 toabout 15 wt. %. The formulation is also preferably “surfactant free.”Alternatively, the formulation may contain one or more surfactants.

A preferred taste masking agent, which facilitates the dissolution ofthe product, and it is believed helps to maintain the amorphous state ofcertain active ingredients such as donepezil, is an aminoalkylmethacrylate copolymer such as that marketed as Eudragit E PO. Theaminoalkyl methacrylate copolymer preferably contains diethylaminoethylresidues, and preferably comprises from about 20 to about 26 wt. % ofsuch groups in a dry substance basis. The average molecular weight ofthe copolymer preferably ranges from about 120,000 to about 180,000, orfrom about 140,000 to about 160,000, most preferably about 150,000.Preferred methacrylic monomers include butyl methacrylate and methylmethacrylate. This agent is preferably present in the final film in anamount of from about 5 to about 25 wt. %, preferably from about 10 toabout 20 wt. %, and more preferably from about 12 to about 18 wt. %. Thecopolymer is preferably micronized to an average particle size less than100, 100, or 10 microns.

Another taste masking agent is a cyclodextrin or derivative thereof.This component is preferably present in the final film in an amount offrom about 10 to about 50 wt. % or, in alternative embodiments, fromabout 10 to about 40 wt. %, or from about 20 to about 35 wt. %.

A preferred stabilizer, especially for donepezil films, is citric acid,especially anhydrous citric acid, and in a preferred embodiment thefinal product comprises from about 0.5 to about 2.0 wt. % citric acid,or from about 0.75 to about 1.25 wt. % citric acid.

Means for Retarding Buccal Absorption (or for Promoting GI Absorption)

Yet another embodiment relates to the orally disintegrating filmsthemselves, and the means incorporated in the films for assuring thatthe active agent is absorbed through the gastrointestinal tract insteadof the oral mucosa. Therefore, in still another embodiment, theinvention provides an orally disintegrating film comprising: (a) anactive pharmaceutical agent that is absorbable through the oral mucosawhen dissolved; and (b) means for retarding absorption of said activepharmaceutical ingredient through the oral mucosa.

The active ingredient from the dosage form is preferably absorbedpredominantly through the gastrointestinal tract. I.e. of the activeingredient absorbed, the predominant amount (greater then 60, 70, 80,90, 95 and up to 100 wt. %) is preferably absorbed through the GI tract.Therefore, the means should be able to deliver greater than 60, 70, 80,90 or 95 and up to 100 wt. % of the active ingredient to thegastrointestinal tract, through the natural process of swallowing, withor without additional water. The formulations can rely on various meansfor retarding absorption of the active ingredient through the oralmucosa, or promoting absorption through the gastrointestinal tract. Themeans should be able to deliver greater than 60, 70, 80, 90 or 95 and upto 100% of the active ingredient to the gastrointestinal tract, throughthe natural process of swallowing, with or without additional water. Forsome drugs, the means may simply comprise the particular film-formingagents employed in the film, and the absence of material quantities ofagents that partition the active agent away from the saliva or thedisintegrated residue toward the mucosal surfaces. For other drugs,which are more permeable through the oral mucosa, or for which only asmall amount of mucosal absorption can be tolerated (due tobioequivalence requirements for the drug), it may be necessary tointegrate a more proactive means for retarding gastrointestinalabsorption, such as ion exchange resins that bind the active agent andprevent its ionization and dissolution upon disintegration of the film;pH adjusting agents that adjust the pH of the environment surroundingthe dosage form to a pH that renders the active agent less permeable;and the use of less permeable salts and bases of active agents.

Suitable ion exchange resins are described generally in H. F. Walton in“Principles of Ion Exchange” (pp. 312 343), and particularly in U.S.Pat. No. 7,067,116 to Bess et al. Preferred ion exchange resins arewater-insoluble and consist of a pharmacologically inert organic orinorganic matrix containing covalently bound functional groups that areionic or capable of being ionized under the appropriate conditions ofpH. The organic matrix may be synthetic (e.g., polymers or copolymers ofacrylic acid, methacrylic acid, sulfonated styrene, sulfonateddivinylbenzene), or partially synthetic (e.g., modified cellulose anddextrans). The inorganic matrix can also be, e.g., silica gel modifiedby the addition of ionic groups. The covalently bound ionic groups maybe strongly acidic (e.g., sulfonic acid), weakly acidic (e.g.,carboxylic acid), strongly basic (e.g., quaternary ammonium), weaklybasic (e.g., primary amine), or a combination of acidic and basicgroups. In general, those types of ion exchangers suitable for use inion exchange chromatography and for such applications as deionization ofwater are suitable for use in these controlled release drugpreparations.

Suitable pH adjusting agents function by ionizing the active agent to aless permeable state. For an acidic active agent, one would adjust thepH of the solution to above the pKa of the active agent to give aneutral species; for a basic active ingredient, one would adjust the pHof the solution to below the pKa of the conjugate acid. Suitable pHadjusting agents for raising the pH of a solution include, for example,sodium carbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, sodium phosphate, potassium phosphate, calcium carbonate,magnesium carbonate, sodium hydroxide, magnesium hydroxide, potassiumhydroxide, and aluminum hydroxide. Suitable pH adjusting agents forlowering the pH of a solution include, for example, weak acids such asthose containing carboxylic acid.

Another method for retarding the buccal absorption of active agent is toincorporate cyclodextrin in the product, particularly alpha-, beta- andgamma-cyclodextrin, derivatives and/or mixtures thereof. This componentis preferably present in the final film in an amount of from about 10 toabout 50 wt. % or, in alternative embodiments, from about 10 to about 40wt. %, or from about 20 to about 35 wt. %.

Another method for retarding the buccal absorption of active agent is toincorporate acrylate polymers, such as Eudragite E PO, Eudragite RS,Eudragite RL, Eudragite L etc. and combinations thereof in the product.These components are preferably present in the final film in an amountof from about 10 to about 50 wt. % or, in alternative embodiments, fromabout 10 to about 40 wt. %, or from about 20 to about 35 wt. %.

Preferred Active Agents

Numerous active agents can be used in the practice of the currentinvention, in various crystalline forms. In a preferred embodiment, theactive ingredient is present in an amorphous state in the final product.Numerous factors can influence the formation and stabilization of theamorphous state in the final product, including the length of polymerused to form the film, the high processing temperature, and the use ofsolvents.

A particularly preferred pharmaceutically active agent for use in thisinvention is donepezil hydrochloride, chemically known as (±)2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride, and represented by the following chemical structure:

Therefore, in one embodiment based upon donepezil, the inventionprovides a donepezil film strip, i.e. a non-mucoadhesive orallydisintegrating film, able to disintegrate upon contact with saliva inthe buccal cavity within about sixty seconds, comprising (±)2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one(donepezil), or a pharmaceutically acceptable salt thereof, incombination with a hydrophilic binder and a water-soluble diluent,wherein: (a) said film comprises from about 2.5 to about 20, preferablyabout 5 or 10, mg of donepezil or a pharmaceutically acceptable saltthereof; (b) donepezil hydrochloride is present in an amount from about0.05% to about 50% (w/w), based on the total weight of the formulation;(c) said film has a T_(max) of from about 3 to about 4 hours, and (d)said donepezil hydrochloride has an absolute bioavailability in saiddosage form of about 100%. The donepezil is preferably present asdonepezil hydrochloride, and the film is preferably characterized by thegeneral formulations described herein.

Other embodiments relate to the use of donepezil film strips in thetreatment of dementia, particularly dementia of the Alzheimer's type.Thus, in yet another embodiment, the invention provides a method oftreating mild to moderate dementia in a human patient comprisingadministering to the tongue of said patient, preferably once daily, thedonepezil films of the present invention. In a preferred embodiment, thetreatment is accompanied by a step that promotes GI absorption of thedonepezil, such as swallowing within about 60 seconds of administration,with or without water.

Various crystalline forms of donepezil hydrochloride are known in theart, including an amorphous state and five crystalline states designatedForms (I) to (V), as described more particularly in U.S. Pat. No.5,985,684. In a particularly preferred embodiment, the donepezilhydrochloride is present in the final formulation substantially orcompletely in an amorphous state, more than 70, 80, 90, 95, 98 or 99%free of other crystalline forms of donepezil hydrochloride. Thecombination of amorphous donepezil and aminoalkyl methacrylate copolymeror a reduced quantity of beta-cyclodextrin has proven particularlyuseful, and results in a film product having excellent physicalproperties. The utility of the amorphous form might be attributable toits reluctance to transform into a solvated form, unlike Form I which,when treated with water, changes its solid state and converts into asolvate form.

In one embodiment the product is manufactured initially from Form I, andresults in a final product that contains predominantly (if notcompletely) amorphous donepezil hydrochloride. It has been found thatusing Form I as the starting material results in a substantially betterfinal product than starting with amorphous donepezil hydrochloridestabilized with known stabilizers, such as e.g. lactose. Therefore instill another embodiment, the invention provides a non-mucoadhesiveorally disintegrating film, able to disintegrate upon contact withsaliva in the buccal cavity within about sixty seconds, comprisingdonepezil hydrochloride in amorphous form, in combination with ahydrophilic binder and a water-soluble diluent, wherein said film ismade by a process comprising: (a) dissolving donepezil hydrochlorideForm I in a film forming base and liquid solvent to form a liquidintermediate; (b) spreading said liquid intermediate on a flat surface;and (c) evaporating said liquid solvent from said liquid intermediate toform said final film product.

Another preferred pharmaceutically active agent is ondansetron,preferably as its base. Ondansetron is chemically known as (±) 1,2,3,9tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one,and its base is represented by the following chemical structure:

Therefore, in another embodiment the invention provides an ondansetronfilm strip, wherein the ondansetron is preferably provided in base formto promote GI absorption of the ondansetron. The invention also providesa non-mucoadhesive orally disintegrating film, able to disintegrate uponcontact with saliva in the buccal cavity within about sixty seconds,comprising (±) 1,2,3,9tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one(ondansetron), in combination with a hydrophilic binder and awater-soluble diluent, and means for promoting gastrointestinalabsorption of said ondansetron, wherein: (a) said means for promotinggastrointestinal absorption comprises ondansetron in base form; (b) saidfilm comprises from about 4 to about 24 mg of ondansetron base; (c)ondansetron base is present in an amount from about 0.05% to about 50%(w/w), based on the total weight of the formulation, (d) said film has aT_(max) of from about 1.5 to about 2.5 hours, and (e) said ondansetronbase has an absolute bioavailability in said dosage form of from about45% to about 75%. The film most preferably contains 4 or 8 mg ofondansetron base, and is preferably formulated according to the generalformulation techniques described in this document.

It is known that ondansetron can exist in several polymorphic forms,including Forms A, B, C, D and E. See WO 03/093260 and WO 2005/080381.It has been unexpectedly found that the crystalline purity of theondansetron in the final product influences the physical properties ofthe final film, and that highly pure form B is particularly preferred.In particular, for films stored at higher temperatures 60° C., physicalchanges in the RapidFilm have been detected, including added rigidity,warps and folding, and these changes are associated with a decrease inpeak intensity and decreased purity of Form B. See FIG. 4 (where OND 013OD refers to a RapidFilm product stored at 40° C., and 84201506 refersto the same formulation stored at 60° C.).

Therefore, in yet another embodiment, the film comprises form Bpolymorph that is essentially free of other polymorphic forms, i.e.greater than 70, 80, 90, 95, 98 or even 99% pure. Form B can beevaluated by X-ray diffraction as described more particularly in Example8. Alternatively or in addition, the product is characterized by amelting endotherm at 244±2° C. when subjected to differential scanningcalorimetry.

In another embodiment, the invention provides methods of using theondansetron film strips of the present invention, for the treatment orprevention of emesis, including emesis resulting from postoperativenausea and vomiting, chemotherapy induced nausea and vomiting, andradiation induced nausea and vomiting. Therefore, the invention alsoprovides a method of treating or preventing emesis in a human patientcomprising administering to the tongue of said patient, preferably fromone to three times daily, an ondansetron film strip of the presentinvention that contains from about 4 to about 24 mg of ondansetron base,preferably 4 or 8 mg of ondansetron base. The method is preferablypracticed with an additional step that promotes gastrointestinalabsorption of said ondansetron, such as swallowing said film withinabout sixty seconds of said administration, with or without water.

Another preferred pharmaceutically active agent is desloratadine,chemically known as 8-chloro,6,11-dihydro-11-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,and has the following chemical structure:

Yet another preferred pharmaceutically active agent is olanzapine,chemically known as2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,and has the following chemical structure:

The amount of pharmaceutically active agent that can be used in thefilms is dependent upon the dose needed to provide an effective amountof the pharmaceutically active agent. Examples of doses for specificpharmaceutically active agents that can be delivered per one strip ofrapidly dissolving oral film are reviewed in Table A, along withpreferred dosing schedules and pharmacokinetic parameters. Reportedpharmacokinetic data is obtained preferably in the fasted state, unlessotherwise stated. Pharmacokinetic profiles by which the formulations ofthe present invention can be measured include AUC (0-∞ or 0-48),T_(max), C_(max), and combinations thereof.

The drugs can also be characterized by their solubility in water at pH1.2, pH 4.0, or pH 6.8, or a combination of pH levels. In particular,the drug may be characterized according to any of the followingsolubility descriptions, as taken from USP 28/NF 23 (2005):

Parts of Solvent Required for Descriptive Term 1 Part of Solute VerySoluble Less than 1 Freely Soluble From 1 to 10 Soluble From 10 to 30Sparingly Soluble From 30 to 100 Slightly Soluble From 100 to 1000 VerySlightly Soluble From 1000 to 10,000 Practically Insoluble, or InsolubleGreater than or equal to 10,000

Particular pharmacokinetic profiles of drugs of interest are set forthbelow in Table A.

TABLE A Preferred Pharmaceutical Preferred Dosing Agent Dose SchedulePreferred Pharmacokinetic Parameters Donepezil HCl 5 mg Once DailyAbsolute Bioavailability = ca. 100% (Aricept ®) 10 mg T_(max) = 3-4Hours Linear Pharmacokinetics over 1-10 mg dose range given once dailyNeither food nor time of administration influences the rate or extent ofabsorption Ondansetron Base 4 mg 1-3 Times Bioavailability in HealthySubjects = ca. 45-75% (Zofran ®) 8 mg Daily, Not To (56% for 8 mgtablet) 24 mg Exceed 24 mg T_(max) = 1.5-2.5 Hours Per Day Plasmaconcentrations are not dose proportionate Bioavailability slightlyenhanced by food Desloratadine 2.5 mg Once Daily T_(max) = 3.0 hours*(Clarinex ®) 5.0 mg Mean Steady State Peak Plasma Conc. = 4 ng/ml* AUC =56.9 ng hr/ml* Food has no effect on C_(max) or AUC Loratadine 10.0 mg10 mg per day (Claritin ®) Cetirizine 5.0 mg 5-10 mg either T_(max) =1.0 hr. (fasted) Hydrochloride 10.0 mg once or twice C_(max) = 311 ng/mlwhen 10 mg tablet (Zyrtec ®) daily administered once daily for ten daysFood delays T_(max) by 1.7 hrs. and decreases C_(max) by 23% Olanzapine2.5 mg 5-20 mg/day T_(max) = 6.0 hours (Zyprexa ®) 5.0 mg AbsoluteBioavailability = ca. 60% 7.5 mg Linear pharmacokinetics over clinicaldosing 10.0 mg range 15.0 mg Food does not affect the rate or extent of20.0 mg absorption. Administration once daily → steady state conc. ca.twice the conc. after single doses Risperidone 0.25 mg 0.25-4.0 mgAbsolute Bioavailability = ca. 70% (CV = 25%) (Risperdal ®) 0.50 mg BIDor QD T_(max) = 1.0 hour 1.0 mg Food does not affect the rate or extentof 2.0 mg absorption. 3.0 mg 4.0 mg Rivastigmine 1.5 mg** 3-12 mg/dayAbsolute Bioavailability = ca. 36% for 3.0 mg Tartrate (Exelon ®) 3.0mg** (1.5-6 mg BID) dose 4.5 mg** T_(max) = 1.0 hours (fasted state) 6.0mg** Administration with food → delays absorption (T_(max)) by 90minutes; lowers C_(max) by ca. 30%; and increases AUC by ca. 30% Linearpharmokinetics up to 3 mg BID Doubling dose from 3 to 6 mg BID → threefold increase in AUC Sildenafil Citrate 25.0 mg** T_(max) = 30-120minutes (60 min. median) (fasted) (Viagra ®) 50.0 mg** C_(max) = ca. 450ng/ml.(fasted) (100 mg dose) 100.0 mg** Administration with high fatmeal → delays absorption (T_(max)) by 60 minutes; lowers C_(max) by ca.29% Absolute bioavailability = ca. 40% Dose proportionalpharmacokinetics Vardenafil HCl 2.5 mg Absolute bioavailability = ca.15% (Levitra ®) 5.0 mg T_(max) = 30-120 minutes (60 min. median)(fasted) 10.0 mg Administration with high fat meal → lowers 20.0 mgC_(max) by ca. 18-50% C_(max) = ca. 10-25 ug/L (ca. 18 ug/L median)(fasted) (20 mg dose) Dose proportional pharmacokinetics Galantamine HBr4.0 mg** 8-16 mg BID Absolute bioavailability −= ca. 90% (Razadyne ®)8.0 mg** Dose proportional pharmacokinetics from 8-32 mg/ 12.0 mg** dayT_(max) = ca. 60 minutes (fasted) Administration with food → delaysabsorption (T_(max)) by 90 minutes; lowers C_(max) by ca. 25%; no changein AUC Diclofenac K 12.5 mg Buprenorphine 2.0 mg** 12-16 mg/day AUC₀₋₄₈(hr · ng/ml) = 32.63 (CV = 25) (16.0 mg) HCl 8.0 mg** Similar plasmaconcentrations of buprenorphone (Subutex ®) as Suboxone ® C_(max) = 5.47ng/ml (CV = 23) (16 mg) Dose proportional pharmacokinetics forbuprenorphine from 4-16 mg/day 1.0, 2.0 and 4.0 mg doses deliverbuprenorphine below limit of quantitation (0.05 ng/ml) after two hoursin seven of eight subjects Buprenorphine 2.0/0.5 mg** 12-16 mg/dayAUC₀₋₄₈ (hr · ng/ml) = 12.52 (CV = 35)(4 mg); HCl/naloxone HCl 8.0/2.0mg** 20.22 (CV = 43)(8 mg); 34.89 (CV = 33)(16 mg) dihydrate C_(max)(ng/ml) = 1.84 (CV = 39) (4 mg); 3.0 (Suboxone ®) (CV = 51)(8 mg); 5.95(CV = 38) (16 mg) Dose proportional pharmacokinetics for buprenorphinefrom 4-16 mg/day 1.0, 2.0 and 4.0 mg doses deliver buprenorphine belowlimit of quantitation (0.05 ng/ml) after two hours in seven of eightsubjects Mean peak naloxone levels range from 0.11 to 0.28 ng/ml in doserange of 1-4 mg Alprazolam 0.25 mg 1, 2, 3, 4, 5, 6, 7, 8, 9, T_(max) =1-2 hours (Xanax ®) 0.5 mg or 10 mg/day, in C_(max) = 8.0-37 ng/ml over0.3-3.0 mg dose range 1.0 mg divided doses Plasma levels proportionateto dose given 2.0 mg (2, 3 or 4 doses/day) Clonazepam 0.125 mg 0.25-4mg/day Absolute bioavailability = ca. 90% (Klonopin ®) 0.25 mg individed doses T_(max) = 1-4 hours 0.5 mg (2, 3 or 4 1.0 mg doses/day)2.0 mg Diazepam 2.0 mg 2.0-10.0 mg/ T_(max) = 30-90 minutes (Valium ®)5.0 mg dose, 2-4 10.0 mg times daily Lorazepam 0.5 mg 1-10, 2-6 or 2-3mg/ Absolute bioavailability = ca. 90% (Ativan ®) 1.0 mg day (1, 2, 3T_(max) = ca. 120 minutes 2.0 mg or 4 doses/day) C_(max) = 20 ng/ml (2mg); dose proportionate among doses Sumatriptan 25.0 mg** One tablet,not C_(max) = 18 ng/ml (range 7-47 ng/ml) (25 mg); 51 ng/ml Succinate50.0 mg** to exceed one (range 28-100 ng/ml) (100 mg) (Imitrex ®) 100.0mg** tablet per hour Absolute bioavailability = ca. 15% C_(max) is sameduring a migraine attack and when migraine free T_(max) = ca. 2.5 hrs.during attack; ca. 2.0 hrs. when migraine free Single dose → doseproportionality in extent of absorption (AUC) over dose range of 25-200mg, but C_(max) is ca. 25% less than expected from 25 mg dose High fatmeal (100 mg tablets) → Cmax and AUC increased by 15% and 12%,respectively *following oral administration of 5 mg once daily for 10days to normal healthy volunteers **base eq.

The anti-migraine class of drugs known as triptans is especially suitedfor use in the dosage forms of the present invention. Sumatriptan(Imitrex®) is chemically designated as3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide. Thesuccinic acid salt of sumatriptan is represented by the followingchemical structure:

For purposes of this invention, sumatriptan can be administered as anypharmaceutically acceptable salt that demonstrates adequate stabilityupon storage and bioavailability upon administration, but a preferredform of sumatriptan for purposes of this invention is sumatriptansuccinate (1:1).

The dosage form preferably comprises from about 15 mg to about 125 mg ofsumatriptan (based on the weight of the base, in whatever form thesumatriptan is present), and more preferably comprises from about 25 mgto about 100 mg of sumatriptan, or about 25 mg, 50 mg or 100 mgspecifically, of sumatriptan (corresponding to 35, 70 or 140 mg ofsumatriptan succinate). The mean maximum concentration following oraldosing with 25 mg is preferably about 18 ng/mL. (with a preferred rangeof from about 7 to about 47 ng/mL), and 51 ng/mL (range, 28 to 100ng/mL) following oral dosing with 100 mg of sumatriptan. In addition,the dosage form preferably yields a T_(max) for the sumatriptan of fromabout 1.5 to about 3.0 hours, preferably from about 2.0 to about 2.5hours, whether determined during a migraine-free period or during anattack.

Eletriptan (Relpax®) is chemically designated as(R)-3-[(1-Methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole,and the hydrobromide salt is represented by the following chemicalstructure:

For purposes of this invention, eletriptan can be administered as anypharmaceutically acceptable salt that demonstrates adequate stabilityupon storage and bioavailability upon administration, but a preferredform of eletriptan for purposes of this invention is eletriptanmonohydrobromide.

The dosage form preferably comprises from about 10 mg to about 100 mg ofeletriptan (based on the weight of the base, in whatever form theeletriptan is present), and more preferably comprises from about 10 mgto about 60 mg of eletriptan, from about 20 to about 40 mg ofeletriptan, or about 20 mg or about 40 mg specifically, of eletriptan(corresponding to 24.2 mg or 48.5 mg of eletriptan hydrobromide). Inaddition, the dosage form preferably yields a T_(max) for the eletriptanof from about 1.0 to about 3.0 hours, preferably about 1.5 to about 2.0hours, whether determined during a migraine-free period or during anattack.

Rizatriptan (Maxalt®) is chemically described asN,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine. Thebenzoic acid salt of rizatriptan is depicted by the following chemicalstructure:

For purposes of this invention, rizatriptan can be administered as thebase or as any pharmaceutically acceptable salt that demonstratesadequate stability upon storage and bioavailability upon administration,but a preferred form of rizatriptan for purposes of this invention isrizatriptan benzoate.

The dosage form preferably comprises from about 2.5 mg to about 15 mg ofrizatriptan (based on the weight of the base, in whatever form therizatriptan is present), and more preferably comprises from about 5 mgto about 10 mg of rizatriptan, or about 5 mg or about 10 mgspecifically, of rizatriptan (corresponding to 7.265 or 14.53 mg ofrizatriptan benzoate). In addition, the dosage form preferably yields at_(max) for the rizatriptan of from about 0.5 to about 3.0 hours,preferably from about 1.0 to about 2.5 hours, whether determined duringa migraine-free period or during an attack.

Other 5-HT_(1B/1D) receptor agonists with which the invention could bepracticed include Zolmitriptan (Zomig®), Naratriptan (Amerge®),Almotriptan (Axert®), and Frovatriptan (Frova®). Other migraine productsthat could be combined with the diclofenac potassium in the dosage formsof the present invention include dihydroergotamine and metoclopramide.

Zolmitriptan is chemically designated as(S)-(4)-[[3-[2-(dimethylamino)ethyl]-1H-indol-5yl]methyl]-2-oxazolidinone,and has the following chemical structure:

The dosage form preferably comprises from about 1.5 mg to about 7.5 mgof zolmitriptan, and more preferably comprises from about 2.5 mg toabout 5.0 mg of zolmitriptan, or about 2.5 mg or about 5.0 mgspecifically, of zolmitriptan. In addition, the dosage form preferablyyields a T_(max) for the zolmitriptan of from about 1.0 to about 4.0hours, preferably from about 1.0 to about 2.0 hours, or from about 2.5to about 3.5 hours, whether determined during a migraine-free period orduring an attack.

Naratriptan is chemically designated asN-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide, andhas the following chemical structure when present as the hydrochloride:

For purposes of this invention, naratriptan can be administered as thebase or as any pharmaceutically acceptable salt that demonstratesadequate stability upon storage and bioavailability upon administration,but a preferred form of naratriptan for purposes of this invention isnaratriptan hydrochloride.

The dosage form preferably comprises from about 0.5 mg to about 5.0 mgof naratriptan (based on the weight of the base, in whatever form thenaratriptan is present), and more preferably comprises from about 1.0 mgto about 2.5 mg of naratriptan, or about 1.0 mg or about 2.5 mgspecifically, of naratriptan (corresponding to 1.11 or 2.78 mg ofnaratriptan hydrochloride). In addition, the dosage form preferablyyields a t_(max) for the naratriptan of from about 1.5 to about 4.5hours, preferably from about 2.0 to about 4.0 hours, whether determinedduring a migraine-free period or during an attack.

Almotriptan malate is chemically designated as1-[[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]sulfonyl]pyrrolidine(±)-hydroxybutanedioate (1:1), and has the following chemical structurewhen present as the malate:

For purposes of this invention, almotriptan can be administered as thebase or as any pharmaceutically acceptable salt that demonstratesadequate stability upon storage and bioavailability upon administration,but a preferred form of almotriptan for purposes of this invention isalmotriptan malate.

The dosage form preferably comprises from about 2.5 mg to about 15.0 mgof almotriptan (based on the weight of the base, in whatever form thealmotriptan is present), and more preferably comprises from about 6.25mg to about 12.5 mg of almotriptan, or about 6.25 mg or about 12.5 mgspecifically, of almotriptan. In addition, the dosage form preferablyyields a T_(max) for the almotriptan of from about 0.5 to about 4.0hours, preferably from about 1.0 to about 3.0 hours, whether determinedduring a migraine-free period or during an attack.

Frovatriptan is preferably administered as the succinic acid salt, in anamount of from about 1.0 to about 5.0 mg, preferably about 2.5 mg (basedon the weight of frovatriptan). In addition, the dosage form preferablyyields a T_(max) for the frovatriptan of from about 0.5 to about 4.0hours, whether determined during a migraine-free period or during anattack.

Other Pharmaceutically Active Agents

The expression “pharmaceutically active agents” as used herein isintended to encompass agents other than foods, which promote astructural and/or functional change in and/or on bodies to which theyhave been administered. These agents are not particularly limited;however, they should be physiologically acceptable and compatible withthe film. Suitable pharmaceutically active agents include, but are notlimited to:

-   -   antimicrobial agents, such as triclosan, cetyl pyridium        chloride, domiphen bromide, quaternary ammonium salts, zinc        compounds, sanguinarine, fluorides, alexidine, octonidine, EDTA,        and the like;    -   non-steroidal anti-inflammatory drugs, such as aspirin,        acetaminophen, ibuprofen, ketoprofen, diclofenac, diflunisal,        fenoprofen calcium, naproxen, tolmetin sodium, indomethacin, and        the like;    -   anti-tussives, such as benzonatate, caramiphen edisylate,        menthol, dextromethorphan hydrobromide, chlophedianol        hydrochloride, and the like;    -   decongestants, such as pseudoephedrine hydrochloride,        phenylepherine, phenylpropanolamine, pseudoephedrine sulfate,        and the like;    -   anti-histamines, such as brompheniramine maleate,        chlorpheniramine maleate, carbinoxamine maleate, clemastine        fumarate, dexchlorpheniramine maleate, diphenhydramine        hydrochloride, diphenylpyraline hydrochloride, azatadine        meleate, diphenhydramine citrate, doxylamine succinate,        promethazine hydrochloride, pyrilamine maleate, tripelennamine        citrate, triprolidine hydrochloride, acrivastine, loratadine,        brompheniramine, dexbrompheniramine, and the like;    -   expectorants, such as guaifenesin, ipecac, potassium iodide,        terpin hydrate, and the like;    -   anti-diarrheals, such as loperamide, and the like;    -   H₂-antagonists, such as famotidine, ranitidine, and the like;    -   proton pump inhibitors, such as omeprazole, lansoprazole, and        the like;    -   general nonselective CNS depressants, such as aliphatic        alcohols, barbiturates and the like;    -   general nonselective CNS stimulants such as caffeine, nicotine,        strychnine, picrotoxin, pentylenetetrazol and the like;    -   drugs that selectively modify CNS function, such as        phenyhydantoin, phenobarbital, primidone, carbamazepine,        ethosuximide, methsuximide, phensuximide, trimethadione,        diazepam, benzodiazepines, phenacemide, pheneturide,        acetazolamide, sulthiame, bromide, and the like;    -   antiparkinsonism drugs such as levodopa, amantadine and the        like;    -   narcotic-analgesics such as morphine, heroin, hydromorphone,        metopon, oxymorphone, levorphanol, codeine, hydrocodone,        xycodone, nalorphine, naloxone, naltrexone and the like;    -   analgesic-antipyretics such as salycilates, phenylbutazone,        indomethacin, phenacetin and the like; and    -   psychopharmacological drugs such as chlorpromazine,        methotrimeprazine, haloperidol, clozapine, reserpine,        imipramine, tranylcypromine, phenelzine, lithium and the like.

Other suitable drugs include ambroxol hydrochloride, apomorphine,ascorbic acid, betamethasone, caffeine, dextromethorphan, glimepiride,hydrocortisone, ketotifen, loperamide, meclozine, melatonin, neramexane,piroxicam, sodium picosulfate, and zinc histidine, and pharmaceuticallyacceptable salts thereof.

The most preferable drugs are those in which a unitary dosage formcomprises no more than about 50 mg, 25 mg, 15 mg or 10 mg of the activeingredient per unit.

Dispensing/Packaging Format

The films of the present invention can be provided in various dispensingand/or packaging configurations. For example, in one embodiment, thefilms would be packaged in a dose card that contains a plurality ofindividually wrapped films protected by moisture impermeable removablelaminar covers. Examples of suitable dose cards are reported, forexample, in U.S. Pat. No. 6,520,329, WO 2006/056161, WO 02/059012, EP 1353 857, and WO 01/62621, the disclosures of which are herebyincorporated by reference.

In another embodiment, the films would be packaged in a hermeticallysealed, moisture impermeable flat pouch comprising two walls adheredaround the edges. In a preferred embodiment, the packaging prevents thedosage form from absorbing more than 4.0, 3.0, 2.0 or even 1.0 wt. %moisture in three months when stored at 40° C. and 75% relativehumidity.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds claimed herein are made and evaluated, and are intended to bepurely exemplary of the invention and are not intended to limit thescope of what the inventors regard as their invention. Efforts have beenmade to ensure accuracy with respect to numbers (e.g., amounts,temperature, etc.) but some errors and deviations should be accountedfor. Unless indicated otherwise, parts are parts by weight, temperatureis in ° C. or is at room temperature, and pressure is at or nearatmospheric.

Example 1 Representative Ondansetron Formulation

Table 1 depicts a representative film formulation that contains 8.0 mgof ondansetron as its base, in order to promote gastrointestinalabsorption.

TABLE 1 Representative Formulation of Ondansetron Base Film Dosage FormAmount per Amount per Pos. Ingredient Film [mg] Film [%] 1 Ondansetron(as base) 8.0 15.84 2 Mowiol 22.0 43.56 (Polyvinylalcohol) 3 PEG(polyethylene glycol) 6.0 11.88 4 Glycerol anhydrous 2.0 3.96 5 RiceStarch 10.0 19.80 6 Acesulfam K 0.2 0.40 7 Titanium dioxide 0.3 0.59 8Menthol 1.0 1.98 9 Polysorbate 1.0 1.98 TOTAL 50.5 100.0

Example 1A Comparative Bioavailability of Zofran Brand Tablets

Tables 2 and 3 present clinical pharmacokinetic data for Zofran® brandimmediate release 8 mg and 24 mg tablets, as reported in the Food andDrug Administration (FDA) approved prescribing information for thisproduct:

TABLE 2 Pharmacokinetics in Normal Volunteers Single 8 mg Zofran ®Tablet Dose Peak Time of Mean Systemic Mean Plasma Peak PlasmaElimination Plasma Age-group Weight Concentration ConcentrationHalf-life Clearance Absolute (years) (kg) n (ng/mL) (h) (h) L/h/kgBioavailability 18-40 M 69.0 6 26.2 2.0 3.1 0.403 0.483 F 62.7 5 42.71.7 3.5 0.354 0.663 61-74 M 77.5 6 24.1 2.1 4.1 0.384 0.585 F 60.2 652.4 1.9 4.9 0.255 0.643 ≧75 M 78.0 5 37.0 2.2 4.5 0.277 0.619 F 67.6 646.1 2.1 6.2 0.249 0.747

TABLE 3 Pharmacokinetics in Normal Volunteers Single 24 mg Zofran ®Tablet Dose Time of Mean Mean Peak Plasma Peak Plasma EliminationAge-group Weight Concentration Concentration Half-life (years) (kg) n(ug/mL) (h) (h) 18-43 M 84.1 8 125.8 1.9 4.7 F 71.8 8 194.4 1.6 5.8

Example 2 Comparative Ondansetron Dissolution Study

Dissolution studies were conducted on five different orally administeredondansetron products: Zofran®4 mg Zydis® Lingual; Zofran® 8 mg Zydis®Lingual; ondansetron 4 mg RapidFilm having the formulation of Table 4;ondansetron 8 mg RapidFilm having the formulation of Table 4 (punched in6 cm² rectangles); and Zofran® 8 mg Filmtablet.

TABLE 4 Ondansetron RapidFilm Formulation Formula dosage form MasterBatch [mg/unit] Ingredients Formula [g/100 g] [3.00 cm³final film]Ondansetron Base 6.8116 4.000 Polyvinylalcohol 4-88 18.7321 11.000 PEG1000 5.1088 3.000 Glycerol anhydr. 1.7032 1.000 Rice starch 8.5149 5.000Acesulfam K 0.1707 0.100 Titanium dioxide 0.2559 0.150 Levomenthol0.8514 0.500 Polysorbate 80 0.8514 0.500 Ethanol 96% 23.7519 RemovedPurified Water 33.2481 Removed

Dissolution studies were performed according to Ph. Eur. 2.9.4, paddle,sinker, 900 ml, using 0.1N HCl buffered water at pH 1.0. Stirringoccurred at 100 rpm and 37° C. Relative pharmacokinetics are reported inTable 5 below and FIG. 1.

TABLE 5 Lot. 5G033 R208046 OND0080D 8 mg 5H010 OND008OD 4 mg Zofran 8 mgZofran 8 mg Ondanaetron Zofran 4 mg Zydia Ondanaetron 4 mg Time Filmtablet Zydis Lingual 8 mg Rapid Film Lingual Rapid Film [min] [%] [%][%] [%] [%] 0 0 0 0 0 0 1 0.8 100.3 97.1 102.3 71.8 3 9 104.6 102 101.798.4 5 22.7 103.4 102.4 101.4 103.3 7 63.4 102.1 101.7 101.3 105 10103.3 100.8 100.8 101.8 105.2

Example 3 Comparative Ondansetron Bioavailability Study

A clinical study was conducted to compare the bioavailability profileand the pharmacokinetic parameters of two medicinal products containing8 mg ondansetron: (1) ondansetron RapidFilm formulated having theformulation reported in Table 4, and (2) Zofran®8 mg. ZydisLingual-Orally Disintegrating Tablets.

The study was a randomized, single dose, two way, two sequencecrossover, open label with seven days washout period study under fastingconditions. Orally disintegrating tablet and RapidFilm was allowed todissolve in the subject's mouth for about 10 seconds before the patientwas asked to swallow. The study included 7 healthy adult Caucasianmales.

Table 6 reports pharmacokinetic and bioequivalence parameters observedduring the study. FIG. 1 is a comparison of dissolution profiles overtime comparing three commercially available formulations of ondansetronwith two ondansetron RapidFilm formulations, as described in Table 4.FIG. 2 depicts mean (FIG. 2A) and log mean (FIG. 2B) drug plasmaconcentration profiles versus time for 8 mg ondansetron RapidFilminvestigational product (Table 4) versus Zofran®8 mg. Lingual orallydisintegrating tablets.

TABLE 6 Investigational Product Reference Product (Algebraic (AlgebraicPharmacokinetic Parameter Mean ± SD) Mean ± SD) C_(max) (ng/ml) 18.75 ±6.262  20.37 ± 6.470 AUC_(0-t) (ng * hr/ml) 94.11 ± 38.078 100.05 ±48.826 AUC_(0-∞) (ng * hr/ml) 98.18 ± 39.345 103.66 ± 49.691 T_(max)(hr) 1.58 ± 0.408  1.71 ± 0.749 T_(lag) (hr) 0.08 ± 0.204  0.08 ± 0.204T_(1/2) (hr) 3.45 ± 0.817  3.62 ± 0.624 K_(elimination) (hr⁻¹) 0.2111 ±0.05284  0.1965 ± 0.03480 (AUC_(0-t)/AUC_(0-∞)) % 95.67 ± 1.467  96.14 ±1.362 BE C_(max) AUC_(0-t) AUC_(0-∞) Assessment Parameter (80.00-125.00)(80.00-125.00) (80.00-125.00) Point Estimate (%) 91.84 96.32 96.79 LowerLimit (%) 72.64 82.87 83.81 Upper Limit (%) 116.13 111.96 111.78 Prob<80.00 0.1389 0.0291 0.0239 Prob >125.00 0.0244 0.0105 0.0096

Example 4 Representative Donepezil Formulations

Table 7 recites the ingredients of a film formulation that contains 10.0mg of donepezil hydrochloride. The formulation lacks any specialingredients for promoting GI absorption, other than the formulation'saffinity for water, and its rapid disintegration in saliva. Table 5describes an alternative formulation of 10.0 mg donepezil hydrochloridethat contains cyclodextrin to retard the absorption of active ingredientthrough the oral mucosa, and thereby promote GI absorption.

TABLE 7 Representative Formulation of Donepezil HCl OrallyDisintegrating Film Amount per Amount per Pos. Ingredient Film [mg] Film[%] 1 Donepezil HCl 10.00 12.27 2 Polyethylenoxide 50.00 61.36 3Polysorbate 80 (Tween 80) 1.00 1.23 4 Glycerol anhydrous 12.00 14.73 5Citric acid anhydrous 1.00 1.23 6 Titanium dioxide 0.50 0.61 7 AcesulfamK 1.50 1.84 8 Anis flavor 1.65 2.02 9 Peppermint flavour 3.84 4.71 TOTAL81.49 100.0

TABLE 8 Alternative Representative Formulation of Donepezil HCl OrallyDisintegrating Film Amount per Amount per Pos. Ingredient Film [mg] Film[%] 1 Donepezil HCl 10.0 9.48 2 β-Cyclodextrin (Cavamax W7) 44.5 42.18 3Polyvinylalkohol (Mowiol 4-88) 30.0 28.44 4 Polyethylenglycol (PEG 1000)8.0 7.58 5 Propylenglycol 5.0 4.74 6 Citric acid anhydrous 1.0 0.95 7Acesulfam K 1.5 1.42 8 Anis flavor 1.65 1.56 9 Peppermint flavour 3.843.64 TOTAL 105.49 100.0

Example 5 Comparative Dissolution Study of Donepezil Formulations

A comparative dissolution study was undertaken to compare thedissolution profile of various RapidFilm products and formulations withcommercially available donepezil products. The formulations for thedonepezil film products are reported in Tables 9-14.

TABLE 9 Donepezil RapidFilm; Prototype A Formula dosage form MasterBatch [mg/unit] Ingredients Formula [g/100 g] [3.00 cm³final film]Donepezil HCI (Form I) 4.2470 5.000 Polyvinylalcohol 4-88 12.7410 15.000PEG 1000 3.3970 4.000 Acesulfam K 0.6370 0.750 β-Cyclodextrine 18.898022.250 Citric Acid anhyd. 0.4250 0.500 Propylenglycol 2.1230 2.500 Anis0.7010 0.825 Peppermint 1.6310 1.920 Purified Water 39.9000 RemovedEthanol abs. 15.3000 Removed

TABLE 10 Donepezil RapidFilm; Prototype B Formula dosage form MasterBatch [mg/unit] Ingredients Formula [g/100 g] [3.00 cm³final film]Donepezil HCI (Form I) 3.0540 5.000 Polyethylenoxide 15.2680 25.000Acesulfam K 0.4580 0.750 Polysorbat 80 0.3050 0.500 Glycerol anhydr.3.6640 6.000 Titanium dioxide 0.1530 0.250 Citric acide monohydrate0.3050 0.500 Anis 0.5040 0.825 Peppermint 1.1730 1.920 Purified Water15.3000 Removed Ethanol abs. 59.8200 Removed

TABLE 11 Donepezil RapidFilm; Prototype C Formula dosage form MasterBatch [mg/unit] Ingredients Formula [g/100 g] [3.00 cm³final film]Donepezil HCI (amorphous) 13.7230 5.000 Lactose 10.2920 15.000Polyvinylalcohol 4-88 10.2920 15.000 PEG 1000 2.7450 4.000 Acesulfam K0.5150 0.750 β-Cyclodextrine 15.2660 22.250 Citric Acid anhyd. 0.34300.500 Propylenglycol 1.7150 2.500 Anis 0.5660 0.825 Peppermint 1.31701.920 Purified Water 41.2000 Removed Ethanol abs. 12.4000 Removed

TABLE 12 Donepezil RapidFilm; Prototype E Formula dosage form MasterBatch [mg/unit] Ingredients Formula [g/100 g] [3.00 cm³final film]Donepezil HCI (Form I) 4.8799 5.000 Polyvinylalcohol 4-88 13.8054 15.000PEG 1000 3.6813 4.000 Acesulfam K 0.6903 0.750 β-Cyclodextrine 11.769111.125 Citric Acid anhyd. 0.4603 0.500 Propylenglycol 2.3008 2.500 Anis0.7783 0.825 Peppermint 1.8022 1.920 Purified Water 43.2660 RemovedEthanol 96% 16.5664 Removed

TABLE 13 Donepezil/Eudragit Pre-Mix for Prototype F Master BatchIngredients Formula [g/100 g] Donepezil HCI (Form I) 12.5000 Eudragit EPO 12.5000 Ethanol abs.*⁾ 75.0000 *⁾not part of the finished product

TABLE 14 Donepezil/Eudragit RapidFilm; Prototype F Formula dosage formMaster Batch [mg/unit] Ingredients Formula [g/100 g] [3.00 cm³finalfilm] Donepezil HCI/Eudragit 10.0000 10.000 combination)Polyvinylalcohol 4-88 15.0000 15.000 PEG 1000 4.0000 4.000 Acesulfam K0.7500 0.750 Propylenglycol 2.5000 2.500 Anis 0.8250 0.825 Peppermint1.9200 1.920 Aqua purificata* 65.0000 Removed *not part of the finishedproduct

Dissolution studies were performed according to Ph. Eur. 2.9.4, paddle,sinker, 900 ml, using 0.1N HCl buffered water at pH 1.0. Stirringoccurred at 50 rpm and 37° C. Relative pharmacokinetics are reported inTable 15 below and FIG. 3.

TABLE 15 Rapid film, Rapid film, Rapid film, Rapid film, Aricept filmTime Prototype A Prototype C Prototype E Prototype F Tablets Aricept ODT[min] [%] [%] [%] [%] [%] [%] 0 0 0 0 0 0 0 3 58.8 86.5 66.8 103.3 14.547.9 5 78.7 101.0 78.3 106.7 40.3 78.9 7 90.0 102.4 86.5 111.3 57.4 89.010 93.7 105.0 94.7 111.0 70.5 93.5 15 94.0 103.1 102.4 111.0 82.1 97.130 93.9 102.9 106.8 111.5 92.9 98.1

Example 6 Representative Diclofenac K Formulation

Table 16 recites the ingredients of a 6 cm² film formulation thatcontains 12.5 mg of diclofenac potassium (matrix weight=120.7 g/m²). Thefilm contains an ion exchange resin to retard the absorption of activeingredient through the oral mucosa, and thereby promote GI absorption.

TABLE 16 Representative Formulation of Diclofenac K OrallyDisintegrating Film Amount per Film Amount per Pos. Ingredient [mg] Film[%] 1 Mowiol 4-88 22.00 30.4 2 PEG 1000 6.00 8.3 3 Neohesperidin DC 0.600.8 4 Duolite AP 143/1093 18.75 25.9 5 Menthol 1.00 1.4 6 Polysorbate 801.50 2.1 7 Ferrum Oxide (No. 3) 0.05 0.1 8 Rice Starch 10.0 13.8 9Diclofenac Potassium 12.5 17.3 TOTAL 72.40 100.0 10 Ethanol 96% (v/v)*50.0 11 Purified Water* 70.0 *Removed by evaporation.

Example 7 Representative Formulations of Other Drugs

Tables 17-37 below present representative formulations of alternativedrugs manufactured according to the present invention.

Ambroxol

Using the following components a laminate with a nominal size of 1 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 17 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 3.333 g3.667 g 0.033 g  8.3 g Ambroxol Poly(vinyl alcohol) 4- Saccharin sodiumEthanol 96% hydrochloride 88 (V/V) 1.000 g 0.100 g 11.7 g PEG 1000Polysorbate 80 Purified water 0.250 g Peppermint oil 0.100 g Eucalyptusoil 1.667 g Rice starch

Apomorphine

Using the following components a laminate with a nominal size of 400.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 18 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 0.228 g2.000 g 0.003 g 3.3 g Apomorphine Poly(vinyl alcohol) 4- NeohesperidinEthanol 96% hydrochloride 88 dihydrochalcone (V/V) 0.533 g 0.003 g 4.7 gPEG 1000 Saccharin sodium Purified water 0.033 g Peppermint oil 0.001 gPatent blue V 0.009 g Titanium dioxide

Ascorbic Acid

Using the following components a laminate with a nominal size of 6 000.0cm² should be obtained. From the dried laminate films with a size of 5.0cm² were punched.

TABLE 19 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 24.000 g24.000 g 0.120 g 42.0 g Ascorbic acid Poly(vinyl alcohol) IF Saccharinsodium Ethanol 96% 14 000 (V/V)  6.000 g 8.400 g 60.0 g PEG 1000 Ricestarch Purified water 0.720 g Black currant flavor 2.400 g Azorubin(Stock solution 1%) 0.420 g Titanium dioxide

Betamethasone

Using the following components a laminate with a nominal size of 1 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 20 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 0.667 g3.667 g 0.050 g  8.3 g Betamethasone Poly(vinyl alcohol) 4- TitaniumEthanol 96% 88 dioxide (V/V) 1.000 g 1.667 g 11.7 g PEG 1000 Rice starchPurified water

Caffeine

Using the following components a laminate with a nominal size of 1 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 21 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 6.667 g2.833 g   0.600 g 20.0 g Caffeine Hydroxypropyl- Glycerol, anhydrousEthanol, cellulose anhydrous 0.950 g 0.1.250 g PEG 1000 Citric acid,anhydrous 0.717 g   0.250 g Povidone Neohesperidin dihydrochalcone

Caffeine

Using the following components a laminate with a nominal size of 4 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 22 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 33.333 g20.000 g 0.333 g 33.3 g Caffeine Poly(vinyl alcohol) 4- NeohesperidinEthanol 96% 88 dihydrochalcone (V/V)  5.333 g 0.333 g 46.7 g PEG 1000Saccharin sodium Purified water 3.333 g Glycerol 85%

Dextromethorphan

Using the following components a laminate with a nominal size of 2 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 23 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 3.333 g10.000 g 0.167 g 16.7 g Dextromethorphan Poly(vinyl NeohesperidinEthanol 96% alcohol) 4-88 dihydrochalcone (V/V)  2.667 g 22.0 g PEG 1000Purified water

Diclofenac

Using the following components a laminate with a nominal size of 2 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 24 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 4.167 g7.333 g 0.200 g 16.7 g Diclofenac Poly(vinyl alcohol) 4- NeohesperidinEthanol 96% potassium 88 (V/V) 2.000 g 0.500 g 23.3 g PEG 1000Peppermint oil Purified water 0.367 g Sicovit (Stock solution 1%) 0.333g Polysorbate 80 3.333 g Rice starch

Glimepiride

Using the following components a laminate with a nominal size of 1 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 25 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 0.500 g5.000 g 0.083 g 8.300 g Glimepiride Poly(vinyl Neohesperidin Ethanol 96%(V/V) alcohol) 4-88 dihydrochalcone 1.333 g 0.033 g 11.700 g PEG 1000Menthyl pyrrolidone Purified water carboxylate 0.833 g Glycerol 85%

Hydrocortisone

Using the following components a laminate with a nominal size of 1 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 26 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 1.867 g3.667 g 4050 g 8.3 g Hydrocortisone Poly(vinyl Titanium dioxide Ethanol96% (V/V) acetate alcohol) 4-88 1.000 g 1.667 g 11.7 g PEG 1000 Ricestarch Purified water

Ketotifen

Using the following components a laminate with a nominal size of 1 500.0cm² should be obtained. From the dried laminate films with a size of 6.7cm² were punched.

TABLE 27 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 0.307 g2.226 g 0.111 g 11.128 g Ketotifen Poly(vinyl Polysorbate 20 Ethanol 96%(V/V) fumarate alcohol) 8-88 4.451 g 4.451 g 15.579 g Poly(vinyl Ricestarch Purified water alcohol) 3-83 0.668 g PEG 1000

Loperamide

Using the following components a laminate with a nominal size of 1 500.0cm² should be obtained. From the dried laminate films with a size of 6.7cm² were punched.

TABLE 28 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 0.445 g2.226 g 0.111 g 11.128 g Loperamide Poly(vinyl Polysorbate 20 Ethanol96% (V/V) hydrochloride alcohol) 8-88 4.451 g 4.451 g 15.579 gPoly(vinyl Rice starch Purified water alcohol) 3-83 0.334 g PEG 1000

Meclozine

sing the following components a laminate with a nominal size of 2 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 29 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 9.888 g5.667 g 0.133 g 9.7 g Meclozine Poly(vinyl Menthol Ethanol 96% (V/V)hydrochloride alcohol) 4-88 1.500 g 0.133 g 13.3 g PEG 1000 Licorizeflavor Purified water 1.000 g Glycerol 2.500 g Rice Starch

Melatonin

sing the following components a laminate with a nominal size of 500.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 30 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 0.417 g2.500 g 0.008 g 2.1 g Melatonin Poly(vinyl Neohesperidin Ethanol 96%(V/V) alcohol) 4-88 dihydrochalcone 0.0667 g 0.008 g 4.2 g PEG 1000Saccharin sodium Purified water 0.042 g Peppermint flavor 0.417 gGlycerol 85% 2.083 g Rice starch 0.058 g Titanium dioxide 0.006 g Patentblue V (Stock solution: 3.1 mg/ml)

Metoclopramide

Using the following components a laminate with a nominal size of 1 000.0cm² should be obtained. From the dried laminate films with a size of 6.7cm² were punched.

TABLE 31 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 1.562 g2.226 g 0.03 g 20.772 g Metoclopramide Hydroypropyl- NeohesperidinEthanol 99% hydrochloride cellulose (V/V) 3.709 g 0.059 g CopolyvidoneMenthol 5.935 g Corn starch

Neramexane

Using the following components a laminate with a nominal size of 500.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 32 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 2.143 g1.833 g 0.017 g 4.2 g Neramexane Poly(vinyl Acesulfame Ethanol 96% (V/V)mesylat alcohol) 4-88 Potassium 0.500 g 0.167 g 5.8 g PEG 1000 Glycerol,Purified water anhydrous 0.025 g Titanium dioxide 0.833 g Rice starch0.012 g Masking flavor 0.045 g Orange flavor 0.083 g Polysorbate 80

Olanzapine

Using the following components a laminate with a nominal size of 628.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 33 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 1.047 g2.304 g 0.021 g 1.5 g Olanzapine Poly(vinyl Acesulfame Ethanol 96% (V/V)alcohol) 4-88 Potassium 0.628 g 4.5 g PEG 1000 Purified water

Piroxicam

Using the following components a laminate with a nominal size of 2 000.0cm² should be obtained. From the dried laminate films with a size of 5.0cm² were punched.

TABLE 34 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 8.000 g11.200 g 16.0 g Piroxicam Poly(vinyl Ethanol 96% (V/V) alcohol) IF 14000 2.800 g 22.4 g PEG 1000 Purified water

Sildenafile

Using the following components a laminate with a nominal size of 1 800.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 35 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 10.534 g8.400 g 0.060 g 12.0 g Sildenafile Poly(vinyl Neohesperidin Ethanol 96%(V/V) citrate alcohol) 4-88 1.950 g 0.030 g 18.8 g PEG 1000 Saccharinsodium Purified water 0.120 g Peppermint oil 0.045 g Polysorbate 80

Sodium Picosulfate

Using the following components a laminate with a nominal size of 1 350.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 36 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 1.125 g4.950 g 0.068 g 11.3 g Sodium Poly(vinyl Neohesperidin Ethanol 96% (V/V)picosulfate alcohol) 4-88 dihydrochalcone 1.350 g 0.068 g 15.8 g PEG1000 Titanium dioxide Purified water 2.250 g Rice starch

Zinc Histidine

Using the following components a laminate with a nominal size of 2 000.0cm² should be obtained. From the dried laminate films with a size of 6.0cm² were punched.

TABLE 37 ACTIVE OTHER INGREDIENT POLYMERS COMPONENTS SOLVENTS 10.443 g7.333 g 0.040 g 30.0 g Zinc Poly(vinyl Acesulfame Purified waterhistidine alcohol) 4-88 potassium dihydrate 1.000 g PEG 1000 4.333 gSodium alginate

Example 8 Methods of Characterizing Crystalline Forms

Instrumentation

X-ray diffraction patterns can be obtained on a Miniflex X-raydiffractometer (Rigayu), by laying the sample on a static sample holder.The goniometer radius is 150 mm.

The X-ray tube has a copper target, with a current intensity of 15 mAand a voltage of 30 kV: the radiation generated by the Cockcroft-Waltonmethod, is constituted by K_(α1)(1.540562 Å) and K_(α2)(1.544398 Å);nickel filter is used for the suppression of K_(β) radiation (1.392218Å).

The detector is a NaI scintillator with a beryllium window. Continuousscanning occurred using a sampling width of 0.01 deg and a scanning rateof 2 deg/minute; 2θ range of 2÷50 deg. The sample holder was amorphousglass, and the sample was pressed with a glass plate.

Differential Scanning calorimetry (DSC) thermograms is carried out witha DSC 821^(e) instrument (Mettler Toledo). Temperature is set at 10°C./minute, and the nitrogen flow at 30 ml/min.

A DSC heating curve for Donepezil HCl Form I is presented in FIG. 5; anX-ray diffraction pattern is presented in FIG. 6. X-ray diffractionpeaks are given in Table 38.

TABLE 38 Peak no. 2theta Flex Width d-value Intensity I/Io 1 5.220 0.18816.9153 1890 80 2 10.140 ***** 8.7163 391 17 3 10.820 ***** 8.1700 44519 4 12.900 0.235 6.8569 1548 66 5 13.340 0.188 6.6317 1203 51 6 13.8400.165 6.3932 777 33 7 14.120 0.141 6.2671 814 35 8 15.060 0.212 5.87801039 44 9 16.360 0.188 5.4137 782 34 10 17.140 0.282 5.1691 756 32 1117.760 0.165 4.9900 891 38 12 19.600 0.141 4.5255 657 28 13 20.060 0.1414.4227 993 42 14 21.440 0.282 4.1411 2366 100 15 22.160 0.259 4.0081 87237 16 22.600 0.141 3.9311 830 36 17 23.220 0.212 3.8275 1095 47 1824.180 0.188 3.6777 1822 78 19 26.660 0.188 3.3409 966 41 20 27.4200.094 3.2500 841 36 21 28.320 0.235 3.1487 786 34 22 29.680 0.094 3.00751047 45 23 31.440 0.141 2.8430 922 39 24 32.040 0.071 2.7911 752 32 2535.320 0.353 2.5391 1305 56

An X-ray diffraction pattern for ondansetron base Form B is depicted inFIG. 7; X-ray diffraction peaks are reported in Table 39.

TABLE 39 Peak no. 2theta Flex Width d-value Intensity I/Io 1 5.560 *****15.8817 477 8 2 7.160 0.188 12.3359 6800 100 3 10.860 0.212 8.1400 503174 4 11.120 0.235 7.9502 3949 59 5 13.140 0.259 6.7322 1855 28 6 14.6400.188 6.0456 2315 35 7 16.320 0.306 5.4269 2690 40 8 17.180 0.212 5.1571968 15 9 20.600 0.188 4.3080 2995 45 10 21.220 0.212 4.1835 2184 33 1122.020 0.141 4.0333 1150 17 12 23.980 0.235 3.7079 3420 51 13 24.6600.259 3.6072 3563 53 14 25.260 0.306 3.5228 5176 77 15 26.500 0.2823.3607 2324 35 16 27.700 0.165 3.2178 1443 22

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. It willbe apparent to those skilled in the art that various modifications andvariations can be made in the present invention without departing fromthe scope or spirit of the invention. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly, with a true scope and spirit of the invention being indicated bythe following claims.

1-22. (canceled)
 23. A non-mucoadhesive orally disintegrating film, ableto disintegrate upon contact with saliva in the buccal cavity withinabout sixty seconds, comprising a defined amount of an activepharmaceutical agent, or a pharmaceutically acceptable salt thereof, ahydrophilic binder and a water-soluble diluent, wherein: a) said film ischaracterized predominantly by gastrointestinal absorption when placedon the tongue, allowed to disintegrate, and subsequently swallowed; b)said film is bioequivalent to an immediate release tablet or capsule ororally dissolving/dispersing tablet (ODT) that comprises said activepharmaceutical agent or a pharmaceutically acceptable salt thereof insaid defined amount; and c) said film comprises from about 0.05% toabout 50% (w/w) of said active pharmaceutical agent, based on the totalweight of the formulation.
 24. The film of claim 23 characterized bygreater than 95% gastrointestinal absorption.
 25. The film of claim 23comprising from about 40% to about 80% (w/w) of one or more ingredientsthat constitute said hydrophilic binder and water soluble diluent. 26.The film of claim 23 wherein said active pharmaceutical agent isselected from: donepezil hydrochloride; ondansetron base; desloratadine;olanzapine; risperidone; rivastigmine tartrate; sildenafil; vardenafil;galantamine; diclofenac potassium; buprenorphine HCl; naloxone HCldehydrate; alprazolam; clonazepam; diazepam; lorazepam; sumatriptan;eletriptan; rizatriptan; zolmitriptan; naratriptan; almotriptan;frovatriptan; cetirizine hydrochloride; loratadine; ambroxolhydrochloride; apomorphine; ascorbic acid; betamethasone; caffeine;dextromethorphan; glimepiride; hydrocortisone; ketotifen; loperamide;meclozine; melatonin; neramexane; piroxicam; sodium picosulfate; andzinc histidine; or a pharmaceutically acceptable salt thereof; or acombination thereof.
 27. The film of claim 23 wherein said immediaterelease tablet or capsule or orally dissolving/dispersing tablet (ODT)is characterized by a time to dissolution for 75% of the activepharmaceutical agent of greater than about twenty minutes, and less thanabout ninety minutes, when tested in a type II dissolution apparatus atpH 2.0 and 37° C. at a paddle speed of 50 rpm.
 28. The film of claim 23,wherein said active pharmaceutical agent is subject to first passmetabolism.
 29. The film of claim 23, further comprising means forpromoting gastrointestinal absorption of said active pharmaceuticalagent.
 30. The film of claim 23, wherein said immediate release tabletor capsule or orally dissolving/dispersing tablet (ODT) is characterizedby (i) predominant gastrointestinal absorption when administered orally,(ii) a first pharmacokinetic profile, and (iii) the presence of saidactive agent in said defined amount; made by a process comprising: a)formulating said film to comprise said active agent in said definedamount and to be characterized by a second pharmacokinetic profile thatis bioequivalent to said first pharmacokinetic profile whendisintegrated orally and absorbed in the gastrointestinal tract; and b)clinically testing said orally administered dosage form and said orallydisintegrating film for bioequivalence.
 31. The film of claim 23 in theform of a single layer.
 32. The film of claim 23 wherein said film doesnot contain a surfactant.
 33. A non-mucoadhesive orally disintegratingfilm, able to disintegrate upon contact with saliva in the buccal cavitywithin about sixty seconds, comprising a defined amount of an activepharmaceutical agent, or a pharmaceutically acceptable salt thereof, ahydrophilic binder and a water-soluble diluent, wherein: a) said film ischaracterized predominantly by gastrointestinal absorption when placedon the tongue, allowed to disintegrate, and subsequently swallowed; b)said film comprises from about 0.05% to about 50% (w/w) of said activepharmaceutical agent, based on the total weight of the formulation; andc) said film has: i) a T_(max) greater than about 4.5 hours; ii) anabsolute bioavailability of greater than about 65%, optionally with aT_(max) greater than about 1.5 hours; iii) an absolute bioavailabilityof from about 45% to about 65%, and a T_(max) of less than 3.0 hours;iv) a T_(max) of from 3.0 to 4.5 hours; or v) a T_(max) of less than 1.0hours.
 34. The film of claim 33, wherein said active agent has a T_(max)greater than about 4.5 hours.
 35. The film of claim 33, wherein saidactive agent has an absolute bioavailability of greater than about 65%,optionally with a T_(max) greater than about 1.5 hours.
 36. The film ofclaim 33, wherein said active agent has an absolute bioavailability offrom about 45% to about 65%, and a T_(max) of less than 3.0 hours. 37.The film of claim 33, wherein said active agent has a T_(max) of from3.0 to 4.5 hours.
 38. The film of claim 33, wherein said active agenthas a T_(max) of less than 1.0 hours.
 39. The film of claim 33 whereinsaid active pharmaceutical agent is selected from: donepezilhydrochloride; ondansetron base; desloratadine; olanzapine; risperidone;rivastigmine tartrate; sildenafil; vardenafil; galantamine; diclofenacpotassium; buprenorphine HCl; naloxone HCl dehydrate; alprazolam;clonazepam; diazepam; lorazepam; sumatriptan; eletriptan; rizatriptan;zolmitriptan; naratriptan; almotriptan; frovatriptan; cetirizinehydrochloride; loratadine; ambroxol hydrochloride; apomorphine; ascorbicacid; betamethasone; caffeine; dextromethorphan; glimepiride;hydrocortisone; ketotifen; loperamide; meclozine; melatonin; neramexane;piroxicam; sodium picosulfate; and zinc histidine; or a pharmaceuticallyacceptable salt thereof; or a combination thereof. 40.-51. (canceled)